Early research hints at why women experience more severe gut pain than men do

Differences in how gut cells respond to hormones may help to explain why women experience more frequent and severe gut pain than men do, a study in mice suggests.

Irritable bowel syndrome (IBS) affects roughly 10% to 15% of people worldwide, with women getting diagnosed with the condition up to twice as often as men do. Symptoms of IBS — which include pain, constipation, diarrhea, gas and bloating — can often flare up in response to triggers, like stress or certain foods. But the reasons behind the disparity between women's and men's IBS rates have remained elusive.

Now, researchers have found that estrogen, the primary female sex hormone, may set off a chain reaction in the gut that makes its nerves more sensitive to pain.

"We've long suspected that female hormones play a role in gut pain, but the exact mechanism was unclear," senior study author David Julius, a neurophysiologist at the University of California, San Francisco, told Live Science. "Our findings show a clear pathway for how estrogen can amplify pain signals."

The study, published Dec. 18 in the journal Science, first compared gut pain responses in male and female mice by recording nerve activity in response to gut stimulation and observing their reactions to mild colon inflation. Both tests showed that female mice had more sensitive guts at baseline.

Removing the mice's ovaries to stop estrogen production reduced this sensitivity to male-like levels, however. And restoring estrogen to normal levels brought back the increased pain response seen in female mice.

To find out where and how estrogen exerts its effects, the team examined different gut cells. Based on earlier work, they expected estrogen receptors to be on enterochromaffin cells, which produce about 90% of the body's serotonin, a chemical messenger involved in activating pain-sensing nerves that send signals to the brain. But surprisingly, the team found estrogen receptors not on enterochromaffin cells, but on specialized, rare cells in the lining of the gut.

When these cells, known as L-cells, detect estrogen, they crank up their production of a receptor called OLFR78. This receptor senses short-chain fatty acids, which are byproducts made when gut bacteria digest food. The addition of extra receptors makes L-cells more sensitive to these byproducts, and in turn, they release more of a hormone that helps tell the brain that the stomach is full immediately after a person eats.

To better understand this chain reaction, the researchers grew miniature models of the gut in the lab. They found that the fullness hormone, called PYY, also signals nearby enterochromaffin cells that then release extra serotonin. That serotonin then activates pain-sensing nerves. This chain reaction set off by estrogen may potentially explain why women experience more severe gut pain than men do.

Experiments in genetically engineered mice that lacked estrogen receptors on L-cells confirmed the cells' role in gut sensitivity, as those mice showed weaker nerve responses and reduced serotonin release compared with mice with intact receptors.

"Since estrogen levels fluctuate with the menstrual cycle, this mechanism provides insight into the changes in IBS severity seen in women," said Marissa Scavuzzo, an assistant professor at the Case Western Reserve University School of Medicine who was not involved in the study.

"It also validates the experiences of higher-estrogen or menstruating patients," she said, "which is important because differences in pain sensation in women have historically been overlooked or dismissed."

The findings, though preliminary, may also inform future therapies for gut pain. "PYY and OLFR78 could be promising targets for treating IBS in women," Julius suggested. The work may also help to explain why "low-FODMAP" diets, which aim to reduce the intake of sugars that feed gut bacteria, can ease IBS symptoms in some patients, he added.

Scavuzzo agreed that the work might point to promising treatments. "By pinpointing PYY and L-cell signaling, this study identifies concrete molecular targets that could guide more precise therapies for IBS," she said.

Additionally, the study "highlights the importance of considering how hormonal changes influence IBS symptoms, not only in menstruating women but also in post-menopausal patients and those receiving hormone therapy as part of gender-affirming care."

Translating these findings from mice to people will require caution. Human guts are more complex than those of mice, and factors such as lifestyle, genetics and gut-microbe diversity can influence individuals' hormone-gut interactions.

"Mouse models give us a starting point," Julius said, "but clinical studies are essential before we can make firm conclusions about human gut pain."